Osteoporosis is a disease characterized by accelerated bone loss and deterioration of structural integrity of bone tissue, which lead to bone fracture susceptibility. This debilitating disease results when the rate of bone resorption by osteoclasts (OCLs) is greater than the rate of bone formation by osteoblasts (OBs). Current evidence shows that appendicular and vertebral bone as well as the craniofacial and oral bone structures are affected, resulting in reduced jawbone mass and periodontal bone loss, which complicates dental treatments. Intermittent parathyroid hormone (PTH) administration is the only FDA-approved therapy that produces bone anabolism and enhances bone injury repair. However, PTH dosing is limited to a short-term use with a relatively low dose due to its adverse hypercalcemic effects and oncogenic potential in bone. Therefore, a better understanding of the molecular and cellular mechanisms underlying the osteoanabolic actions and adverse effects of PTH is required to devise strategies to enhance PTH therapy. We hypothesize that the activation of the extracellular calcium-sensing receptors (CaSR) in the OB lineages are essential steps in producing osteoanabolic responses to intermittent PTH at appendicular and craniofacial sites and that combined treatment with a calcimimetic will enhance the osteoanabolic effects of intermittent PTH by simultaneously potentiating CaSR activities in OBs in normal and fracture bones. To test this hypothesis, a pharmacological approach will be taken to determine whether activating CaSRs in OBs by co-injecting the calcimimetic NPS-R568 enhances osteoanabolism of PTH in mouse models of aging and estrogen deficiency without producing hypercalcemia. This application aims to establish whether calcimimetics enhance anabolism of intermittent PTH by extending its anabolic window and/or by increasing its capacity to build bone. This will be achieved by assessing temporal changes in structural bone parameters, bone-forming and bone-resorbing rates histomorphometrically, numbers of stem cells in bone, and serum bone turnover markers. A loss-of- function approach using an OB-specific CaSR-KO mouse model with the combined regimens followed by biochemical and skeletal analysis will be taken to ascertain whether CaSR expression is required for (i) the growth, survival, and maturation of early OBs, and (ii) the mineralizing functions of mature OBs in the response of the cells to PTH and combined PTH/calcimimetic treatments. Using similar methods, it will be determined whether co-administration of NPS-R568 and PTH produces more robust healing of tibial and mandibular fractures than administration of PTH alone in adult mice. This work will reveal novel synergistic actions of intermittent PTH and Ca2+ in producing skeletal anabolism and establish preclinical regimens to restore osteoporotic skeleton and accelerate bone fracture repair.